The pathogenetic mechanisms responsible for the induction of hepatocellular injury and viral clearance in hepatitis B virus (HBV) infection remain to be determined. Considerable indirect evidence suggests that HBV specific cellular immune response plays a central role in these processes. Proof of this hypothesis is lacking because the appropriate model systems to test it have not existed. Furthermore, if the hypothesis is correct, the pathogenetically relevant HBV encoded target antigens are entirely unknown. The reagents, systems and expertise necessary to assess the role of the immune response in injury and clearance now exist in our laboratory. Therefore, the long term objective of this proposal is to characterize the human cellular immune response to the known HBV-encoded antigens in an effort to delineate the factors potentially involved in viral clearance and liver disease. The study will focus on the characteristics of HBV antigen specific T cell lines and clones derived from the site of infection and injury (liver) and also from the peripheral blood of patients with acute or chronic hepatitis-B. HBV antigen-specific T cells will be assessed for phenotype, fine specificity, HLA restriction and function by testing antigen specific helper, suppressor and cytotoxic activities and lymphokine production. Our preliminary results indicate that HBV nucleocapsid specific T cells present in the peripheral blood do not accurately reflect events occurring within the liver at the site of injury and viral synthesis. We, therefore, intend to expand these studies to the remaining HBV encoded antigens in this proposal. When such data is available it will be possible to determine if HBV antigen specific T cell activation, phenotype and function are pathogenetically related to virus induced injury and to viral clearance.